CEA is the best characterized human tumor-associated antigen and the most widely used tumor marker for the in vitro diagnosis of human colon cancers. CEA, however, is one of a family of closely related genes including normal cross-reacting antigen (NCA) and biliary glycoprotein (BGPI).
Many antibodies to tumor markers cross-react with related antigens. Accordingly, the development of antigen-specific monoclonal antibodies (MABs) for in vitro and in vivo diagnosis and therapy requires a good knowledge of the number, quality and biodistribution of related cross-reactive antigens. This requirement has restricted the number of acceptable tumor markers which, in the case of colon cancer, includes CEA, CA 17-1A and TAG-72.
Careful immunochemical characterization of the MAB to be used is required with respect to its specificity and affinity for the target antigen and for related antigens. Systematic application of a MAB that is cross-reactive with a related antigen must be avoided to foreclose risk of potentially severe side effects.
Murine MAB T84.66 (ATCC Accession No. BH 8747) IgG1,k shows a high affinity constant (2.6.times.10.sup.10 M.sup.- 1) and no cross reactivity to other members of the CEA gene family. T84.66 is therefore ideally suited for immunodetection and immunotherapy studies.
Use of murine MABs including T84.66 for detection and therapy of human tumors is constrained by patient immune response against the heterologous immunoglobulin. The production of human anti-mouse antibodies (HAMA) leads to reduced efficiency of the MAB and to potentially serious manifestations of acute and chronic allergic complications for the patient. See Levy, et al. Ann. Rev. Med. 34:107-116 (1983); Houghton, et al. Proc. Natl. Acad. Sci. USA, 82:1242-1246 (1985) and Sears, et al. J. Biol. Resp. Modifiers 3:138-150 (1984).
Recombinant DNA technology provides attractive methods to generate MABs useful to circumvent such problems from chimeric human/non-human genes. In addition, recombinant antibody genes provide a renewable source of antibodies which can be further engineered to alter affinity constants and effector functions. Using different approaches, a number of antibody genes and derivatives thereof have been constructed which code for antibody chimeras directed against tumor-associated antigens. Sahagen, et al, J.Immunol. 137:1066-1074 (1986); Sun, et al., Proc.Natl.Acad.Sci.USA 84:214-218 (1987); Nishimura, et al., Cancer Res. 47:999-1005 (1987); Liu, et al. Proc.Natl.Acad. Sci.USA 84:3439-3443 (1987).
Beidler, et al, J. Immunology 141:4053-4060 (1988) describe a murine/human chimeric antibody constructed by using variable light and variable heavy regions from a murine hybridoma CEM231.6.7 specific for CEA. The parental hybridoma bound antigen with an affinity of 5.times.10.sup.9 M.sup.-1, chimeric subclones bound antigen at 2.times.10.sup.10 M.sup.-1, and 1.times.10.sup.10 M.sup.-1. Clinical utility of the chimera, including lack of cross-reactivity was not demonstrated.